This application is a 371 of PCT/98/02846 filed May. 13, 1998.
The possibility to improve the permeation of drugs through the biolocical barrieres such as mucosa or skin, to make the drugs coming into the blood circulation, has been always studied by the pharmaceutical researchers.
Specifically the administration of drugs for systemic absorption through the skin presents some basic advantages, e.g. over the oral route. Among these, the scarce variability of the systemic absorption basically determined by the skin permeation of the drug, which avoids some critical factors of the oral absorption, such as gastric acidity, intestinal motility, presence and quality of food, metabolic demolition of the drug by the liver.
Moreover the transdermic administration of drugs is particularly well suited for long term continous treatments and to avoid side effects related to some drugs. To achieve these goals many different inventions have been prosed based on different technological and scientific approaches.
For example biphasic multicomponent systems such as microemulsions have been proposed; microemulsions can be defined as xe2x80x9coptically transparent and thermodynamically stable mixtures, containing two non-mixable components, such as water and oilxe2x80x9d ( Schulman, J. H., Stoeckenius W., Prince L. M., Journal of Physical Chemistry, 63, 1677, 1959 ). To obtain such microemulsions four components must be used: 1) dispersed or internal phase; 2) dispersing or external phase; 3) surfactant and 4) cosurfactant, mixed together in molar ratios defined through psudo-ternary plots (Schwuger M., Stickdorn K., Chemical Rewies, 95, 849-864, 1995.
In some specific cases the components can be less than three, more often above four. There can be xe2x80x9coil in waterxe2x80x9d or xe2x80x9cwater in oilxe2x80x9d microemulsions; Usually oil means lipophilic liquids which cannot be mixed with water, such as organic solvents, oils, fatty acids, whereas water means polar and hydrophilic liquids which can be mixed with water.
B. W. Muller describes, in U.S. Pat. No. 4,719,239 , a multicomponent system, liquid and transparent, for pharmaceutical use, aimed for percutaneous, peoral and transmucosal absorption. In such a system the drug is solubilized either in the oil or water phase, in presence of physiologically acceptable surfactants and cosurfactants, and wherein in certain condition the cosurfactant can assume the function of the oil, or the last can act as surfactant.
The above mentioned patent claims for improvement of percutaneous absorption, compared to other multicomponent systems.
Swiss Pat. Appl. 81-CH0002327 Sandoz based on invention so called microemulsion, claims the obtention of a prolonged percutaneous administration (3 days ) thanks to a reservoir effect.
Eur. Pat. Application 135171 A (Hoffmann-Laroche) claims similarly to U.S. Pat. No. 4,719,239 a pharmaceutical carrier called xe2x80x9cpseudo-monophasexe2x80x9d, consisting of a surfactant (HPL 12-15) soluble in both oil and water phases, with percentages in the range of 5-45%. Such carrier, able to originate percutaneous administration of interferon, can be defined as an oil-water microemulsion and shows an improved diffusion through the skin.
The topical administration for systemic use (via transdermal) of ionic drugs can benefit from biphasic compositions of different kinds, among which the above described microemulsions.
Swiss Patent Appl. CH-86-2597/86 8 (Ciba -Geigy), describes in general, some compositions (such us cream, ointment and gel) which however do not include microemulsions, in particular refers to the anionic drug Diclofenac or its salts (sodic, potassium salt, diethylammonium salt). This patent claims for pharmaceutical compositions comprising Diclofenac or its salt for pharmaceutical use, a percutaneous asorption promoter, of defined chemical formula (ammide tri-substituted), liquid paraffin at body temperature and suitable pharmaceutical excipient.
An important limit to these biphasical compositions called xe2x80x9cmicroemulsionsxe2x80x9d is represented by the necessity of formulating the composition according to definite percentages rate of component substances, as shown from diagrams of pseudo-ternary phase. This relative composition, that allows the forming of the liquid system, anisotropic and transparent, defined as xe2x80x9cmicroemulsionxe2x80x9d, is essentially not modifiable because the addition or the substraction of one of the four components (I-IV) out of the component concentration limits will alterate the system, with separation of phases and destruction of the system itself, while substitution of one of the components will originate a system with different characteristics. As consequence, absorption or transdermal permeation of an active principle, released from microemulsion, depends on the composition of the system itself: the dissolved drug will partition itself into the two phases, oil (lipophilic) and water (hydrophilic), in relation to its coefficient of oil/water partitioning. Permeation rate and absorption of drug is therefore determined by the composition and the possibility of modifying such a rate without changing completely the composition of the microemulsion results virtually not realizable.
The present invention refers to a drug multicomponent biphasical composition that enables to solve the problems of prior art. In particular the present invention refers to a drug composition consisting of an oil phase and a water phase, comprising typically four essential components, defined as (I) dispersed or internal phase, (II) dispersing or external phase, (III) surfactant and (IV) cosurfactant, mixed together in molar ratios determined by the pseudo-ternary phase diagrams and moreover containing a drug (V) and characterized in that it furtherly comprises one compound (VI) able to modify the partitioning coefficient of the drug between oil and water phase, consequently influencing the rate of permeation through the skin. Furthermore the compound (VI) can, in some unexpected cases, form specific complexes with the drug modifying its concentration in the phases of the biphasic system and directly influencing transdermal permeation of the drug itself.